Global and Local Reactivity Descriptors Based on Quadratic and Linear Energy Models for α,β-Unsaturated Organic Compounds

Abstract

<div>Global and local descriptors of chemical reactivity can be derived from conceptual density functional theory. Their explicit form, however, depends on how the energy is defined as a function of the number of electrons. Within the existing interpolation models, here, the quadratic and the linear energy model were used to derive global descriptors as the electrophilicity and nucleophilicity (defined as the negative of the ionization potential) and local descriptors employing either the corresponding condensed fukui function in the linear model or the local response of the global descriptor in the quadratic model. The ability of these descriptors to predict the reactivity of molecules with more than one reactive site was first studied on a set of α ,β -unsaturated ketones, where experimental rate constants for the nucleophilic attack is known. With the validated descriptors the reactivity of α ,β -unsaturated carboxylic compounds with different heteroatoms as α ,β -unsaturated thioesters, esters and amides as alternative substrates for the enzymatic CO<sub>2</sub> fixation studied experimentally by Erb <i>et al.</i> was addressed. The carbon dioxide fixation involves the reduction of the neutral α ,β -unsaturated carboxylic compounds by a nucleophilic attack of a hydride anion from NADPH and the following electrophilic attack by carbon dioxide. It was found that condensed values of the linear fukui function within the fragment of molecular response approximation describe best the reactivity of α ,β -unsaturated ketones. For the two relevant processes involved in CO<sub>2</sub> fixation the amides present the largest reactivity in vacuum and in aqueous solution compared to the esters and thioesters and may, therefore, serve as alternative sustrates of carboxylases.</div>

Atom Condensed Fukui Function for Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide

“…In our previous study, we have shown that the condensed Fukui functions under the fragment molecular response (FMR) approach with the Hirshfeld-I partitioning method correctly describes the reactivity of α, β unsaturated systems as the crotonyl thioester. 33 Recently, our findings were further confirmed independently also by others. 34,35 Here, we use the validated local reactivity descriptor to analyze the crotonyl test system in different conformations and molecular environments as a vacuum, aqueous solution, and in the enzyme.…”

“…The reactivity of the crotonyl thioester as the enzyme substrate model was studied with local reactivity descriptors based on conceptual DFT as the Fukui function [11][12][13] within the linear energy model. The chosen approximations for the Fukui function and the method to condense it to atoms were validated in our previous study on the electrophilicity and nucleophilicity of α, β unsaturated esters, amides, and thioesters 33 and are summarized here briefly.…”

“…36 This combination of methods reproduced correctly the reactivity of α, β unsaturated systems as reported in our previous study. 33 The weight function of atom A used to partition the electron density is…”

Atom Condensed Fukui Function for Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide

“…The reactivity of the crotonyl thioester as the enzyme substrate model was studied with local reactivity descriptors based on conceptual DFT as the Fukui function [11][12][13] within the linear energy model. The chosen approximations for the Fukui function and the method to condense it to atoms were validated in our previous study on the electrophilicity and nucleophilicity of α, β unsaturated esters, amides, and thioesters 33 and are summarized here briefly.…”

Machine Learning Meets Mechanistic Modelling for Accurate Prediction of Experimental Activation Energies

“…32 From conceptual DFT, we used the global electrophilicity descriptor ω and nucleophilicity descriptor N, as well as the corresponding local nucleophilicity and electrophilicity descriptors ℓN and ℓω. 33 These electronic features were complemented with atomic charges (q) from the DDEC6 scheme 34 and the electrostatic potential at the nuclei (VN) of the reactive atoms. 35 In terms of sterics and dispersion, we use the ratio of solvent accessible surface area (SASAr) 36 of the reactive atoms and the universal quantitative dispersion descriptor Pint.…”